JP2008523102A5

JP2008523102A5 -

Info

Publication number: JP2008523102A5
Application number: JP2007545718A
Authority: JP
Filing date: 2005-12-12
Publication date: 2009-02-12

Claims

A pharmaceutical composition for treating or preventing airway inflammation, comprising the PDE4 modulator, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

The pharmaceutical composition according to claim 1, further comprising at least one second active agent.

The second active agent is an antibiotic, anticholinergic agent, antihistamine, anti-inflammatory agent, antioxidant, antitussive, β ₂ -agonist, calcium channel blocker, corticosteroid, immunomodulator, immunosuppressant A drug, leukotriene inhibitor, monoclonal antibody, mucolytic agent, muscle relaxant, PDE4 inhibitor, potassium channel opener, prostaglandin or analog, sensory neuropeptide release inhibitor, tachykinin antagonist, or theophylline or derivative thereof, claim Item 3. A pharmaceutical composition according to Item 2.

The pharmaceutical composition according to claim 1, wherein the stereoisomer of the PDE4 modulator is enantiomerically pure.

2. The PDE4 modulator is (+)-2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione. The pharmaceutical composition as described.

The PDE4 modulator is cyclopropyl-N- {2-[(1S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -3-oxoisoindoline-4-yl} 2. The pharmaceutical composition according to claim 1, which is carboxamide.

The PDE4 modulator is cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonyl-ethyl] -3-oxo-2,3-dihydro-1H-isoindole-4 2. The pharmaceutical composition according to claim 1, which is -yl} -amide.

8. The pharmaceutical composition of claim 7, wherein the PDE4 modulator is enantiomerically pure.

The pharmaceutical composition according to claim 1, wherein the PDE4 modulator has the following formula (I):

Wherein n has a value of 1, 2, or 3;
R ⁵ is unsubstituted o-phenylene, or nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, O-phenylene substituted with 1 to 4 substituents each independently selected from the group consisting of alkyl having 1 to 10 carbon atoms, alkyl having 1 to 10 carbon atoms, and halo;
R ⁷ is (i) phenyl or nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl having 1 to 10 carbon atoms, carbon Phenyl substituted by one or more substituents each independently selected from the group consisting of alkoxy having 1 to 10 alkoxy and halo, (ii) unsubstituted benzyl, nitro, cyano , Trifluoromethyl, carbooxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, and halo Benzyl substituted with 1-3 substituents selected from: (iii) naphthyl, and (iv) benzyl Ruoxy;
R ¹² is —OH, alkoxy having 1 to 12 carbon atoms, or the following formula:

;
R ⁸ is a hydrogen atom or an alkyl having 1 to 10 carbon atoms; and
R ⁹ is a hydrogen atom, alkyl having 1 to 10 carbon atoms, —COR ¹⁰ , or —SO ₂ R ¹⁰ , where R ¹⁰ is a hydrogen atom, alkyl having 1 to 10 carbon atoms, or phenyl It is. ).

10. The pharmaceutical composition according to claim 9, wherein the PDE4 modulator is enantiomerically pure.

The pharmaceutical composition according to claim 1, wherein the PDE4 modulator has the following formula (II):

Wherein each of R ¹ and R ² is, independently of one another, a hydrogen atom, lower alkyl, or R ¹ and R ² together with the illustrated carbon atom to which each is attached, substituted O-phenylene, o-naphthylene, or cyclohexene-1,2-diyl, or nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, Substituted with 1 to 4 substituents independently selected from the group consisting of alkylamino, dialkylamino, acylamino, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, and halo O-phenylene, o-naphthylene, or cyclohexene-1,2-diyl;
R ³ is nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl having 1 to 10 carbon atoms, 1 to 10 carbon atoms Of alkoxy, alkylthio having 1 to 10 carbon atoms, benzyloxy, cycloalkoxy having 3 to 6 carbon atoms, C ₄ -C ₆ -cycloalkylidenemethyl, C ₃ -C ₁₀ -alkylidenemethyl, indanyloxy, And phenyl substituted with 1 to 4 substituents selected from the group consisting of halo;
R ⁴ is a hydrogen atom, alkyl having 1 to 6 carbon atoms, phenyl, or benzyl;
R ^{4 ′} is a hydrogen atom or an alkyl having 1 to 6 carbon atoms;
R ⁵ _{_{is, -CH 2 -, - CH 2}} -CO -, - SO 2 -, - S-, or a -NHCO-; and
n has a value of 0, 1, or 2. ).

12. The pharmaceutical composition of claim 11, wherein the PDE4 modulator is enantiomerically pure.

The pharmaceutical composition according to claim 1, wherein the PDE4 modulator has the following formula (III):

(In the formula, carbon atoms indicated by * constitute a chiral center;
Y is C═O, CH ₂ , SO ₂ , or CH ₂ C═O;
Each of R ¹ , R ² , R ³ and R ⁴ independently of one another is a hydrogen atom, halo, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, nitro, cyano, hydroxy, Or —NR ⁸ R ⁹ ; or any ^two of R ¹ , R ² , R ^3, and R ⁴ on adjacent carbon atoms, together with the illustrated phenylene ring, are naphthylidene;
Each of R ⁵ and R ⁶ is independently of one another a hydrogen atom, an alkyl having 1 to 4 carbon atoms, an alkoxy having 1 to 4 carbon atoms, a cyano, or a cycloalkoxy having up to 18 carbon atoms ;
R ⁷ is hydroxy, alkyl having 1 to 8 carbon atoms, phenyl, benzyl, or NR ^{8 ′} R ^{9 ′} ;
Each of R ⁸ and R ⁹ is, independently of one another, a hydrogen atom, alkyl having 1 to 8 carbon atoms, phenyl, or benzyl, or one of R ⁸ and R ⁹ is a hydrogen atom, and The other is —COR ¹⁰ or —SO ₂ R ¹⁰ , or R ⁸ and R ⁹ together are tetramethylene, pentamethylene, hexamethylene, or —CH ₂ CH ₂ X ¹ CH ₂ CH ₂ — (formula In which X ¹ is -0-, -S- or -NH-); and
Each of R ^{8 ′} and R ^{9 ′} independently of one another is a hydrogen atom, alkyl having 1 to 8 carbon atoms, phenyl, or benzyl, or one of R ^{8 ′} and R ^{9 ′} is a hydrogen atom; And the other is —COR ^{10 ′} or —SO ₂ R ^{10 ′} or R ^{8 ′} and R ^{9 ′} together are tetramethylene, pentamethylene, hexamethylene, or —CH ₂ CH ₂ X ² CH ₂ CH ₂ — (wherein X ² is —0—, —S— or —NH—). ).

14. The pharmaceutical composition of claim 13, wherein the PDE4 modulator is enantiomerically pure.

A pharmaceutical composition for treating or preventing an airway or lung disease or disorder comprising a PDE4 modulator or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the airway or lung disease or disorder Said pharmaceutical composition wherein the disorder is giant emphysematous cyst, acute bronchitis, chronic bronchitis, emphysema, reversible obstructive airway disease, nocturnal asthma, exercise-induced bronchospasm, or interstitial pulmonary fibrosis.

Respiratory or pulmonary disease comprising a PDE4 modulator or a pharmaceutically acceptable salt, solvate or stereoisomer thereof and a second active agent or a pharmaceutically acceptable salt, solvate or stereoisomer thereof Or a pharmaceutical composition for treating or preventing a disorder;
The respiratory tract or lung disease or disorder is respiratory failure, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, giant emphysematous cyst, acute bronchitis, chronic bronchitis, emphysema, reversible obstructive airway disease, night Asthma, exercise-induced bronchospasm, or interstitial pulmonary fibrosis; and the second active agent is an antibiotic, an anticholinergic agent, an antihistamine, an anti-inflammatory agent, an antioxidant, an antitussive, β ₂ -agonists, calcium channel blockers, corticosteroids, immunomodulators, immunosuppressants, leukotriene inhibitors, monoclonal antibodies, mucolytic agents, muscle relaxants, PDE4 inhibitors, potassium channel openers, prostaglandins or analogs, The pharmaceutical composition, which is a sensory neuropeptide release inhibitor, a tachykinin antagonist, or theophylline or a derivative thereof.

17. The pharmaceutical composition of claim 16, wherein the stereoisomer of the PDE4 modulator is enantiomerically pure.